Abstract
The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.
| Original language | English |
|---|---|
| Pages (from-to) | 179-200 |
| Number of pages | 22 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 144 |
| DOIs | |
| Publication status | Published - Jan 20 2018 |
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Keywords
- Aminoarylthiazole
- CFTR
- Corrector
- Cystic fibrosis
- QSAR
- VX809
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
Cite this
Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. / Liessi, Nara; Cichero, Elena; Pesce, Emanuela; Arkel, Maria; Salis, Annalisa; Tomati, Valeria; Paccagnella, Matteo; Damonte, Gianluca; Tasso, Bruno; Galietta, Luis J.V.; Pedemonte, Nicoletta; Fossa, Paola; Millo, Enrico.
In: European Journal of Medicinal Chemistry, Vol. 144, 20.01.2018, p. 179-200.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools
AU - Liessi, Nara
AU - Cichero, Elena
AU - Pesce, Emanuela
AU - Arkel, Maria
AU - Salis, Annalisa
AU - Tomati, Valeria
AU - Paccagnella, Matteo
AU - Damonte, Gianluca
AU - Tasso, Bruno
AU - Galietta, Luis J.V.
AU - Pedemonte, Nicoletta
AU - Fossa, Paola
AU - Millo, Enrico
PY - 2018/1/20
Y1 - 2018/1/20
N2 - The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.
AB - The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.
KW - Aminoarylthiazole
KW - CFTR
KW - Corrector
KW - Cystic fibrosis
KW - QSAR
KW - VX809
UR - http://www.scopus.com/inward/record.url?scp=85038861439&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85038861439&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.12.030
DO - 10.1016/j.ejmech.2017.12.030
M3 - Article
C2 - 29272749
AN - SCOPUS:85038861439
VL - 144
SP - 179
EP - 200
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -